Abstract Gastric and Gastroesophageal junction (GEJ) cancers are a leading cause of cancer mortality. Despite the development of newer chemotherapies, the response rates and median survival in patients with these tumors has remained essentially stagnant. Defining host and molecular/biologic tumor characteristics to customize treatment may lead to improved survival outcomes. Retrospective studies have identified genetic markers that predict treatment outcome. However, there have been no prospective studies in gastric and GEJ cancer evaluating the clinical utility of these genetic factors. We hypothesize that genomically based treatment will improve the expected response rate in patients with gastric and GEJ cancers. We propose a prospective, multi-institutional Phase II clinical trial testing a germline polymorphism in the thymidylate synthase (TS) gene, the number of tandem repeats in the TS enhancer region (TSER) as a treatment selection marker. The polymorphic variant conferring three tandem repeats (TSER*3) has been associated with 5-FU resistance due to high tumor TS expression in comparison to the TSER*2 variant (two tandem repeats). The TSER*3 polymorphism is common (allelic frequency of 0.5-0.8). In the proposed study, we will prospectively genotype patients with gastric and GEJ cancers. Patients who are expected to be 5-FU sensitive (carrying a TSER*2 allele) will receive a 5-FU containing regimen (5-FU, leucovorin, oxaliplatin). Patients who are expected to be 5-FU resistant (homozygous for TSER*3) will not be included in the study. In Aim 1, we will determine whether treatment selection based on germline TSER polymorphism status improves the response rate in patients with metastatic gastric and GEJ tumors. The response rate obtained from this study will be compared to previously observed response rates in non-genotype selected patients. In Aims 2 and 3, additional correlative studies are proposed to identify confounding factors that may alter the expected outcomes of this treatment approach (e.g. loss of heterozygosity of a tumor TS allele and variations in other genes involved in response/toxicity of the administered treatment). Prospective confirmation of the significance of TSER status as an important prognostic factor in this small, rapidly accruable study may provide sufficient rationale for larger prospective confirmatory trials. The eventual goal of this approach is the reliable use of genetic markers in customizing cancer treatment. Cancers of the stomach and gastroesophageal junction (GEJ) are a significant public health problem and are increasing in incidence at a greater rate than any other cancers. At the time of diagnosis, most patients with these cancers have advanced disease and a dismal rate of survival (~ 0 % at 5 years). Despite newer chemotherapy drugs, the treatment outcomes in these patients have stagnated, therefore new approaches are needed. Pharmacogenomically guided selection of chemotherapy for the treatment of gastric and GEJ cancer is a promising approach to identify patients who are most likely to benefit from a particular chemotherapy. The results of the proposed study will be important to provide solid scientific evidence to justify a larger study that may eventually lead to the use genetic markers in customizing cancer treatment. [unreadable] [unreadable] [unreadable]